Use of insulin sensitisers for treating renal diseases

ABSTRACT

A method of treatment and/or prophylaxis of renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease, and micoralbuminuria which comprises the administration of an effective, non-toxic amount of an insulin sensitizer to a human or non-human mammal in need thereof.

[0001] This invention relates to a novel method for the treatment ofrenal diseases.

[0002] European Patent Applications, Publication Numbers: 0306228,0008203, 0139421, 0032128, 0428312, 0489663, 0155845,0257781, 0208420,0177353, 0319189, 0332331, 0332332, 0528734, 0508740; InternationalPatent Application, Publication Numbers 92/18501, 93/02079, 93/22445 andU.S. Pat. No. 5,104,888, disclose certain thiazolidinedione derivativeswhich are disclosed as having hypoglycaemic and hypolipidaemic activity.The thiazolidinedione derivatives disclosed in these patent applicationsare examples of a class of hypoglycaemic agent generally referred to as‘insulin sensitisers’ and hence these compounds are referred to hereinas ‘thiazouidinedione insulin sensitisers’.

[0003] Another series of compounds generally recognised as havinginsulin sensitiser activity are those typified by the compoundsdisclosed in International Patent Applications, Publication NumbersWO93/21166 and WO94/01420. These compounds are herein referred to as‘acyclic insulin sensitisers’. Other examples of acyclic insulinsensitisers are those disclosed in U.S. Pat. No. 5,232,945 andInternational Patent Applications, Publication Numbers WO92/03425 andWO91/19702.

[0004] Examples of other insulin sensitisers are those disclosed inEuropean Patent Application, Publication Number 0533933, Japanese PatentApplication Publication Number 05271204 and U.S. Pat. No. 5,264,451.

[0005] We have now discovered that compounds having insulin sensitiseractivity can prevent hydronephrosis and proteinuria, such asalbuminuria, and that they are therefore of potential use in thetreatment and/or prophylaxis of renal disease, especially renal diseaseassociated with the development of Type II diabetes including diabeticnephropathy, glomerulonephritis, glomerular sclerosis, nephroticsyndrome, hypertensive nephrosclerosis and end stage renal disease. Theprophylactic action of an insulin sensitiser upon nephropathy is alsoindicative that an insulin sensitising agent can be expected to prevent,reverse, stabilise or retard the progression of microalbuminuria toalbuminuria. This is because microalbuminuria is considered to be apredictor of future nephropathy, especially in patients with clinicalevidence of pre-diabetic insulin resistance syndrome, alternativelyreferred to as Syndrome X.

[0006] Accordingly, the present invention provides a method for thetreatment and/or prophylaxis of renal diseases including diabeticnephropathy, glomerulonephritis, glomerular sclerosis, nephroticsyndome, hypertensive nephrosclerosis and end stage renal disease, andmicroalbuminuria which method comprises the administration of aneffective, non-toxic amount of an insulin sensitiser to a human ornon-human mammal in need thereof.

[0007] Particular insulin sensitisers include thiazolidinedione insulinsensitisers.

[0008] Particular insulin sensitisers include acyclic insulinsensitisers.

[0009] One favoured group of insulin sensitisers are thethiazolidinedione insulin sensitisers disclosed in EP 0306228 andWO94/05659. Thus in a favoured aspect the present invention provides amethod for the treatment and/or prophylaxis of renal diseases includingdiabetic nephropathy, glomerulonephritis, glomerular sclerosis,nephrotic syndrome, hypertensive nephrosclerosis and end stage renaldisease, and microalbuminuria which method comprises the administrationof an effective non-toxic amount of a compound of formula (I):

[0010] or a tautomeric form thereof and/or a pharmaceutically acceptablesalt thereof, and/or a pharmaceutically acceptable solvate thereof,wherein:

[0011] A¹ represents a substituted or unsubstituted aromaticheterocyclyl group;

[0012] R¹ represents a hydrogen atom, an alkyl group, an acyl group, anaralkyl group, wherein the aryl moiety may be substituted orunsubstituted, or a substituted or unsubstituted aryl group;

[0013] R² and R³ each represent hydrogen, or R² and R³ togetherrepresent a bond;

[0014] A² represents a benzene ring having in total up to fivesubstituents; and n represents an integer in the range of from 2 to 6;to a human or non-human mammal in need thereof.

[0015] Suitable aromatic heterocyclyl groups of the compounds of formula(I) include substituted or unsubstituted, single or fused ring aromaticheterocyclyl groups comprising up to 4 hetero atoms in each ringselected from oxygen, sulphur or nitrogen.

[0016] Favoured aromatic heterocyclyl groups of the compounds of formula(I) include substituted or unsubstituted single ring aromaticheterocyclyl groups having 5 to 7 ring atoms, preferably 5 or 6 ringatoms.

[0017] In particular, the aromatic heterocyclyl groups of the compoundsof formula (I) comprise 1, 2 or 3 heteroatoms, especially 1 or 2,selected from oxygen, sulphur or nitrogen.

[0018] Suitable values for A¹ when it represents a 5- membered aromaticheterocyclyl group include thiazolyl and oxazolyl, especially oxazolyl.

[0019] Suitable values for A¹ when it represents a 6- membered aromaticheterocyclyl group include pyridyl or pyrimidinyl, especially pyridyl.

[0020] Preferably, A¹ represents a moiety of formula (a), (b) or (c):

[0021] wherein:

[0022] R⁶ and R⁷ each independently represents a hydrogen or halogenatom, an alkyl or alkoxy group or a substituted or unsubstituted arylgroup or when R⁶ and R⁷ are each attached to adjacent carbon atoms, thenR⁶ and R⁷ together with the carbon atoms to which they are attached forma benzene ring wherein each carbon atom represented by R⁶ and R⁷together is substituted or unsubstituted; and in the moiety of formula(a) X¹ represents oxygen or sulphur.

[0023] Aptly, A¹ represents a moiety of the abovedefined formula (a).

[0024] Aptly, A¹ represents a moiety of the abovedefined formula (b).

[0025] Aptly, A¹ represents a moiety of the abovedefined formula (c).

[0026] A particular form of moiety (c) is a moiety (c′):

[0027] wherein R⁶ and R⁷ are as defined in relation to formula (c).

[0028] In one favoured aspect R⁶ and R⁷ together represent a moiety offormula (d):

[0029] wherein R^(8a) and R^(8b) each independently represent hydrogen,halogen, substituted or unsubstituted alkyl or alkoxy.

[0030] Suitably, R^(8a) and R^(8b) each independently representhydrogen, halogen, alkyl or alkoxy. Favourably, R^(8a) representshydrogen. Favourably, R^(8b) represents hydrogen. Preferably, R^(8a) andR^(8b) both represent hydrogen.

[0031] In a further favoured aspect R⁶ and R⁷ each independentlyrepresent hydrogen, alkyl or a substituted or unsubstituted phenyl groupand more favourably, R⁶ and R⁷ each independently represent hydrogen,alkyl or phenyl.

[0032] Preferably, for the moiety of formula (a), R⁶ and R⁷ togetherrepresent the moiety of formula (d).

[0033] Preferably, for the moieties of formula (b), (c) or (c′), R⁶ andR⁷ both represent hydrogen.

[0034] It will be appreciated that the five substituents of A² includethree optional substituents. Suitable optional substituents for themoiety A² include halogen, substituted or unsubstituted alkyl or alkoxy.

[0035] Further suitable, favoured and preferred values for variables A²,R¹, R², R³and n are as defined in EP 0306228 and WO94/05659.

[0036] A preferred compound of formula (I) is5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dioneor a tautomeric form thereof and/or a pharmaceutically acceptable saltthereof, especially a maleic acid salt thereof, and/or apharmaceutically acceptable solvate thereof.

[0037] As indicated above, a compound of formula (I) may exist in one ofseveral tautomeric forms, all of which are encompassed in the method ofthe present invention. It will be appreciated that the present inventionencompasses the administration of all of the isomeric forms of thecompounds of formula (I) and the pharmaceutically acceptable saltsthereof, including any stereoisomeric forms thereof, whether asindividual isomers or as mixtures of isomers.

[0038] Suitable substituents for any heterocyclyl group of the compoundsof formula (I) include up to 4 substituents selected from the groupconsisting of: alkyl, alkoxy, aryl and halogen or any two substituentson adjacent carbon atoms, together with the carbon atoms to which theyare attached, may form an aryl group, preferably a benzene ring, andwherein the carbon atoms of the aryl group represented by the said twosubstituents may themselves be substituted or unsubstituted.

[0039] The suitable, favoured and preferred thiazolidinedione insulinsensitisers disclosed in European Patent Applications, PublicationNumbers: 0306228, 0008203, 0139421, 0032128, 0428312, 0489663, 0155845,0257781, 0208420, 0177353, 0319189,0332331, 0332332, 0528734,0508740;International Patent Application, Publication Numbers 92/18501,93/02079, 93/22445 and U.S. Pat. No. 5,104,888 are those compoundsdefined as suitable, favoured and preferred in the respective patentpublications.

[0040] The suitable, favoured and preferred acyclic insulin sensitisersdisclosed in International Patent Applications, Publication NumbersWO91/19702, WO92/03425, WO93/21166 and WO94/01420 and U.S. Pat. No.5,232,945 are those compounds defined as suitable, favoured andpreferred in the respective patent publications.

[0041] Other suitable, favoured and preferred insulin sensitisers arethe suitable, favoured and preferred compounds disclosed in EuropeanPatent Application, Publication Number 0533933, International PatentApplication, Publication Number WO93/02079, Japanese Patent ApplicationPublication Number 05271204 and U.S. Pat. No. 5,264,451.

[0042] Also specifically included in the method of the invention are thespecific examples disclosed in the above mentioned patent applications.

[0043] When used herein the term ‘insulin sensitiser’ relates tocompounds which increase the biological response to insulin. Inaddition, based upon the observed effects in appropriate test animalssuch as Zucker fatty (fa/fa) rats, insulin sensitisers are indicated tolower elevated fasting plasma insulin concentrations and improveglycaemic control.

[0044] When used herein the term ‘aryl’ includes phenyl and naphthyloptionally substituted with up to five, preferably up to three, groupsselected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, amino,nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy,or alkylcarbonyl groups.

[0045] When used herein the term ‘halogen’ refers to fluorine, chlorine,bromine and iodine; preferably chlorine.

[0046] When used herein the terms ‘alkyl’ and ‘alkoxy’ relate to groupshaving straight or branched carbon chains,containing up to 12 carbonatoms.

[0047] When used herein the term ‘acyl’ includes alkylcarbonyl groups.

[0048] Suitable alkyl groups are C₁₋₁₂ alkyl groups, especially C₁₋₆alkyl groups e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutylor tert-butyl groups.

[0049] Suitable substituents for any alkyl group include those indicatedabove in relation to the term “aryl”.

[0050] Suitable pharmaceutically acceptable salts include salts ofcarboxy groups and acid addition salts.

[0051] Suitable pharmaceutically acceptable salts of carboxy groupsinclude metal salts, such as for example aluminium, alkali metal saltssuch as lithium, sodium or potassium, alkaline earth metal salts such ascalcium or magnesium and ammonium or substituted ammonium salts, forexample those with lower alkylamines such as triethylamine, hydroxyalkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine ortri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine,or with procaine, dibenzylpiperidine, N-benzyl-b-phenethylamine,dehydroabietylamine, N,N′-bisdehydroabietylamine, glucamine,N-methylglucamine or bases of the pyridine type such as pyridine,collidine, quinine or quinoline.

[0052] Suitable acid addition salts include pharmaceutically acceptableinorganic salts such as the sulphate, nitrate, phosphate, borate,hydrochloride and hydrobromide and pharmaceutically acceptable organicacid addition salts such as acetate, tartrate, maleate, citrate,succinate, benzoate, ascorbate, methane-sulphonate, a-keto glutarate anda-glycerophosphate, especially the maleate salt.

[0053] Suitable pharmaceutically acceptable solvates include hydrates.

[0054] The active compounds disclosed in the above mentioned patentpublications, and referred to herein as insulin sensitisers, includingthe specific examples disclosed therein, are conveniently preparedaccording to the methods disclosed in the said patent publications: Thusa compound of formula (I), or the tautomeric form thereof, and/or apharmaceutically acceptable salt thereof, and/or a pharmaceuticallyacceptable solvate thereof, may be prepared using the processesdescribed in EP 0306228 and WO94/05659.

[0055] The salts and/or solvates of the compounds of formula (I) may beprepared and isolated according to conventional procedures for examplesodium salts may be prepared by using sodium methoxide in methanol.

[0056] The present invention also provides an insulin sensitiser,such asa compound of formula (I), or a tautomeric form thereof and/or apharmaceutically acceptable salt thereof and/or a pharmaceuticallyacceptable solvate thereof, for use in the treatment of and/orprophylaxis of renal diseases including diabetic nephropathy,glomerulonephritis, glomerular sclerosis, nephrotic syndrome,hypertensive nephrosclerosis and end stage renal disease, andmicroalbuminuria.

[0057] The present invention also provides an insulin sensitiser,such asa compound of formula (I), or a tautomeric form thereof and/or apharmaceutically acceptable salt thereof and/or a pharmaceuticallyacceptable solvate thereof, for use in the manufacture of a medicamentfor the treatment and/or prophylaxis of renal diseases includingdiabetic nephropathy, glomerulonephritis, glomerular sclerosis,nephrotic syndrome, hypertensive nephrosclerosis and end stage renaldisease, and microalburminuria.

[0058] In the above mentioned treatment and or prophylaxis the insulinsensitiser such as a compound of formula (I), or a tautomeric formthereof and/or a pharmaceutically acceptable salt thereof and/or apharmaceutically acceptable solvate thereof, may be administered per seor, preferably, as a pharmaceutical composition also comprising apharmaceutically acceptable carrier.

[0059] Accordingly, the present invention also provides a pharmaceuticalcomposition for the treatment and/or prophylaxis of renal diseasesincluding diabetic nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, hypertensive nephrosclerosis and endstage renal disease, and microalbuminuria which composition comprises aninsulin sensitiser, such as a compound of the formula (I), or atautomeric form thereof, or a pharmaceutically acceptable salt thereof,or a pharmaceutically acceptable solvate thereof, and a pharmaceuticallyacceptable carrier therefor.

[0060] As used herein the term ‘pharmaceutically acceptable’ embracescompounds, compositions and ingredients for both human and veterinaryuse: for example the term ‘pharmaceutically acceptable salt’ embraces aveterinarily acceptable salt.

[0061] The composition may, if desired, be in the form of a packaccompanied by written or printed instructions for use.

[0062] Usually the pharmaceutical compositions of the present inventionwill be adapted for oral administration, although compositions foradministration by other routes, such as by injection and percutaneousabsorption are also envisaged

[0063] Particularly suitable compositions for oral administration areunit dosage forms such as tablets and capsules. Other fixed unit dosageforms, such as powders presented in sachets, may also be used.

[0064] In accordance with conventional pharmaceutical practice thecarrier may comprise a diluent, filler, disintegrant, wetting agent,lubricant, colourant, flavourant or other conventional adjuvant.

[0065] Typical carriers include, for example, microcrystallinecellulose, starch, sodium starch glycollate, polyvinylpyrrolidone,polyvinylpolypyrrolidone, magnesium stearate, sodium lauryl sulphate orsucrose.

[0066] Most suitably the composition will be formulated in unit doseform. Such unit dose will normally contain an amount of the activeingredient in the range of from 0.1 to 1000 mg, more usually 0.1 to 500mg, and more especially 0.1 to 250 mg.

[0067] Conveniently, the active ingredient may be administered as apharmaceutical composition hereinbefore defined, and this forms aparticular aspect of the present invention.

[0068] In the above mentioned treatments an insulin sensitiser, such asa compound of the formula (I), or a tautomeric form thereof and/or apharmaceutically acceptable salt thereof and/or a pharmaceuticallyacceptable solvate thereof, may be taken in doses, such as thosedescribed above, one to six times a day in a manner such that the totaldaily dose for a 70 kg adult will generally be in the range of from 0.1to 6000 mg, and more usually about 1 to 1500 mg, generally about 0.5 to10 mg. That is in the range of from 1.429×10⁻³ to 85.714 mg/kg/day, moreusually about 1.429×10⁻² to 21.429 mg/kg/day, generally about 7.143×10⁻³to 0.1429 mg/kg/day.

[0069] The followinlg Examples illustrate the invention but do not limitit in any way.

[0070] Example 1: Studies Into The Effects Of The Test Compound UponRenal Pathology

[0071] Obese Zucker rats are known to develop chronic nephropathy inaddition to hyperlipidaemia, hyperinsulinaemia and peripheral insulinresistance (Kasiske et al 1985).

[0072]5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione(herein after referred to as ‘test compound’) was administered to 2-3month old obese Zucker fa/fa rats by dietary administration to provide adaily dose over a period of 3 months ranging from 2.0 - 7.0 μmole/kgbody weight. A group of age-matched obese Zucker fa/fa rats were giventhe same diet without the addition of the test compound, as was a groupof lean Fa/? rats. At the end of the study, all of the control Zuckerfa/fa rats had chronic nephropathy which involved dilated tubules,atrophied or hyperplastic tubular epithelial cells, thickened tubularbasement membranes, segmented glomeruli or global glomerulosclerosis.

[0073] In the corresponding lean animals, 3/15 animals, a minimal degreeof chronic nephropathy was seen.

[0074] Treatment with test compound resulted in a reduction in theincidence and degree of chronic nephropathy compared to the controlgroup of Zucker fa/fa rats.

[0075] In the kidneys of the control Zucker fa/fa rats, mild-moderatehydronephrosis was seen in 4/9 animals. Characteristically this involveddilation of the kidney pelvis. No hydronephrosis was seen in the ratstreated with test compound. TABLE OF SIGNIFICANT HISTOPATHOLOGICALFINDINGS IN THE KIDNEY OF FATTY ZUCKER RATS Group/Treatment AnimalNumber Hydronephrosis Chronic Nephropathy Group 1 Test Compound in diet 2 0 ±  7 0 ±  9 0 0 15 0 ++ 16 0 ± 17 0 + 21 0 ± 22 0 ± 24 0 ± 27 0 ±28 0 ± Group 2 Diet only  3 ++ +  5 +++ + 13 0 + 14 ++ ++ 18 0 + 23 +++++ 26 0 + 29 0 + 30 0 ++

[0076] Example 2: Studies Into The Effect Of Test CompoundsUpon SystolicBlood Pressure, Urinary Total Protein And Urinary N-Acetylβ-D-Glucosaminidase (NAG) Activity Measurments.

[0077] A second study was performed in Zucker rats over a period of 9months to investigate the longitudinal effects of the drug on systolicblood pressure and various indices of renal function, two of which areexemplified here. In one arm of the study, the drug was given in thediet (50 μmole/kg of diet) from aged 6-7weeks in Zucker fatty (fa/fa)rats, whilst in a second arm of the study, drug treatment as above wasdelayed until proteinuria had become established after 4 months,indicative of structural damage already present in the kidneys. A thirdgroup of Zucker fatty rats and a further group of lean rats were givendiet alone throughout the period of study.

[0078] After dosing with the test compound, at monthly intervalsmeasurements were made of systolic blood pressure, urinary total proteinand urinary N-acetyl βD-glucosaminidase (NAG) activity.

[0079] Measurement of Systolic Blood Pressure

[0080] Rats were enclosed in custom-built restrainers and placed on ashelf in a warming cabinet, whose temperature was controlled atapproximately 30° C. An inflatable cuff with integral pulse sensor wasattached to the tail of each rat. After warming for 20-30 min the tailcuff was inflated and deflated automatically and a measurement ofsystolic blood pressure made using an IITC Non-Invasive Blood PressureMonitor. This cycle was repeated several times for each rat until stablevalues of blood pressure were obtained.

[0081] Measurement of Urinary Parameters

[0082] Twenty-four hour urine collections, made in metabolism cages,were aliquoted and frozen at −70° C. until required for assay.

[0083] (i) Urinary Protein

[0084] Urinary protein concentration was measured using the Bio-Radprotein assay as modified for use in a 96-well microtitre plate. Theassay is a dye-binding assay based on the differential colour change ofa dye in response to various concentrations of protein (Bradford, Anal.Biochem.,72, 248, 1976). After a period of incubation with Dye Reagent,diluted urine samples are read at an optical density of 595 nm using aMolecular Devices multiplate reader.

[0085] (ii) Urinary NAG Activity

[0086] NAG activity was assayed using a reagent kit on a Hitachi 717analyser (both suppied by Boehringer Mannheim UK, Lewes). Enzymeactivity was measured by monitoring the rate of chlorophenol (570 nm)released from the substrate chlorophenol red-β-D-glucosaminide.

[0087] Results and Statistics

[0088] In the tables below, results are given as mean values for thegroup±the standard error of the mean. Results have been analysed by oneway ANOVA and significant differences from the Zucker fatty rat controlgroup have been indicated by an asterisk.

[0089] Conclusion

[0090] The results of Example 2 demonstrate that treatment of Zuckerfatty (fa/fa) rats from the age of 6-7 weeks, for a period of 9 months,with BRL 49653 given via the diet, prevented the development ofhypertension and markedly reduced both the elevation of urinary NAGactivity and the rate of development of proteinuria. When drug treatmentwas commenced after proteinuria had become established, both systolicblood pressure and urinary NAG activity were prevented from risingfurther and again there was a marked reduction of the rate of increasein the urinary protein concentration.

[0091] Effects of starting treatment with Test Compound prior to thedevelopment of renal complications.

SYSTOLIC BLOOD PRESSURE (mm Hg)

[0092] Treatment Zucker fatty rats Zucker fatty rats Lean rats DurationTest Compound Control Control (months) (50 μmol/kg of diet) (powderedchow) (powdered chow) 0 102 ± 3  106 ± 3 123 ± 3* 1 110 ± 3* 120 ± 4 128± 3  2 122 ± 4* 137 ± 4 132 ± 4  3 122 ± 4* 142 ± 6 134 ± 3  4 126 ± 6*146 ± 4 132 ± 4* 5 131 ± 4* 157 ± 6 138 ± 4* 6 128 ± 3* 150 ± 6 133 ± 2*7 125 ± 6* 157 ± 6 128 ± 6* 8 133 ± 5* 155 ± 4 130 ± 3* 9 143 ± 4* 164 ±4 136 ± 3*

[0093] Effects of starting treatment with Test Compound prior to thedevelopment of renal complications

URINARY PROTEIN CONCENTRATION (μg/hour)

[0094] Treatment Zucker fatty rats Zucker fatty rats Lean rats DurationTest Compound Control Control (months) (50 μmol/kg of diet) (powderedchow) (powdered chow) 0 226 ± 15* 287 ± 17  198 ± 19* 1 373 ± 22  355 ±18  321 ± 23* 2 402 ± 22* 509 ± 28  396 ± 20* 3 221 ± 32*  874 ± 102 393 ± 25* 4 376 ± 54* 3965 ± 731  613 ± 52* 5 1573 ± 105* 5823 ± 8091395 ± 88* 6 1585 ± 147*  8946 ± 1171 1192 ± 92* 7 2124 ± 293* 12052 ±1535 1176 ± 96* 8 2664 ± 370* 14534 ± 1540 1409 ± 92* 9 3152 ± 515*16182 ± 1581  1373 ± 113*

[0095] Effects of starting treatment with Test Compound prior to thedevelopment of renal complications.

URINARY N-ACETYL -β- D-GLUCOSAMINIDASE ACTIVITY (mU/hour)

[0096] Treatment Zucker fatty rats Zucker fatty rats Lean rats DurationTest Compound Control Control (months) (50 μmol/kg of diet) (powderedchow) (powdered chow) 0 5.7 ± 0.4   5.9 ± 0.3 4.4 ± 0.3* 1 7.5 ± 0.7  9.1 ± 0.8 5.1 ± 0.5* 2 3.8 ± 1.1*  8.2 ± 1.5 6.5 ± 0.3  3 4.5 ± 0.9* 8.2 ± 1.0 5.2 ± 0.4* 4 5.1 ± 1.2*  9.3 ± 0.5 6.9 ± 0.5* 5 6.5 ± 0.7*10.7 ± 0.4 7.6 ± 0.7* 6 6.5 ± 1.1* 10.8 ± 1.7 7.4 ± 0.5  7 8.9 ± 0.8*11.7 ± 0.7 7.1 ± 0.5* 8 6.2 ± 1.2* 11.8 ± 1.3 7.4 ± 0.5* 9 9.1 ± 1.2*13.4 ± 0.8 7.7 ± 0.6*

[0097] Effects of starting treatment with Test Compound once renalcomplications have become established.

SYSTOLIC BLOOD PRESSURE (mm Hg)

[0098] Treatment Zucker fatty rats Zucker fatty rats Lean rats DurationTest Compound Control Control (months) (50 μmol/kg of diet) (powderedchow) (powdered chow) −4 106 ± 3  106 ± 3 123 ± 3* −3 123 ± 5  120 ± 4128 ± 3  −2 138 ± 7  137 ± 4 132 ± 4  −1 141 ± 6  142 ± 6 134 ± 3   0146 ± 4  146 ± 4 132 ± 4*  1 140 ± 5* 157 ± 6 138 ± 4*  2 134 ± 3* 150 ±6 133 ± 2*  3 144 ± 3* 157 ± 6 128 ± 6*  4 139 ± 3* 155 ± 4 130 ± 3*  5146 ± 6* 164 ± 4 136 ± 3*

[0099] Effects of starting treatment with Test Compound once renalcomplications have become established.

URINARY PROTEIN CONCENTRATION (μg/hour)

[0100] Treatment Zucker fatty rats Zucker fatty rats Lean rats DurationTest Compound Control Control (months) (50 μmol/kg of diet) (powderedchow) (powdered chow) −4 220 ± 13  287 ± 17 198 ± 19* −3 347 ± 32  355 ±18 321 ± 23* −2 457 ± 21  509 ± 28 396 ± 21* −1 958 ± 194  874 ± 102 393± 25*  0 3520 ± 905  3965 ± 731 613 ± 52*  1 3692 ± 386* 5823 ± 809 1395± 88*   2 5326 ± 967*  8946 ± 1171 1192 ± 92*   3 6230 ± 835* 12052 ±1535 1178 ± 96*   4 5379 ± 708* 14534 ± 1540 1409 ± 92*   5 7677 ± 825*16182 ± 1581 1373 ± 113*

[0101] Effects of starting treatment with Compound once renalcomplications have become established.

URINARY N-ACETYL-β-D-GLUCOSAMINIDASE ACTIVITY (mU/hour)

[0102] Treatment Zucker fatty rats Zucker fatty rats Lean rats DurationTest Compound Control Control (months) (50 μmol/kg of diet) (powderedchow) (powdered chow) −4 5.4 ± 0.2   5.9 ± 0.3 4.4 ± 0.3* −3 8.3 ± 0.5  9.1 ± 0.8 5.1 ± 0.5* −2 9.5 ± 1.1   8.2 ± 1.5 6.5 ± 0.3  −1 7.8 ± 0.6  8.2 ± 1.0 5.2 ± 0.4*  0 7.6 ± 0.7*  9.3 ± 0.5 6.9 ± 0.5*  1 7.6 ± 0.7*10.7 ± 0.4 7.6 ± 0.7*  2 5.7 ± 0.9* 10.8 ± 1.7 7.4 ± 0.5   3 7.4 ± 0.9*11.7 ± 0.7 7.1 ± 0.5*  4 5.4 ± 1.0* 11.8 ± 1.3 7.4 ± 0.5*  5 8.0 ± 1.1*13.4 ± 0.8 7.7 ± 0.6*

1. A method for the treatment and/or prophylaxis of renal diseasesincluding diabetic nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, hypertensive nephrosclerosis and endstage renal disease and microalbuminuria which method comprises theadministration of an effective, non-toxic amount of an insulinsensitiser to a human or non-human mammal in need thereof.
 2. A methodaccording to claim 1 , wherein the insulin sensitiser is athiazolidinedione insulin sensitiser.
 3. A method according to claim 1 ,wherein the insulin sensitiser is an acyclic insulin sensitiser.
 4. Amethod according to claim 1 , wherein the insulin sensitiser is acompound of formula (I):

or a tautomeric form thereof and/or a pharmaceutically acceptable saltthereof, and/or a pharmaceutically acceptable solvate thereof, wherein:A¹ represents a substituted or unsubstituted aromatic heterocyclylgroup; R¹ represents a hydrogen atom, an alkyl group, an acyl group, anaralkyl group, wherein the aryl moiety may be substituted orunsubstituted, or a substituted or unsubstituted aryl group; R² and R³each represent hydrogen, or R² and R³ together represent a bond; A²represents a benzene ring having in total up to five substituents; and nrepresents an integer in the range of from 2 to 6; to a human ornon-human mammal in need thereof.
 5. A method according to claim 4 ,wherein in the compound of formula (I) A¹ represents a moiety of formula(a), (b) or (c):

wherein: R⁶ and R⁷ each independently represents a hydrogen or halogenatom, an alkyl or alkoxy group or a substituted or unsubstituted arylgroup or when R⁶ and R⁷ are each attached to adjacent carbon atoms, thenR⁶ and R⁷ together with the carbon atoms to which they are attached forma benzene ring wherein each carbon atom represented by R⁶ and R⁷together is substituted or unsubstituted; and in the moiety of formula(a) X¹ represents oxygen or sulphur.
 6. A method according to claim 5 ,wherein in the compound of formula (I) A¹ represents a moiety of theabove defined formula (c).

wherein R⁶ and R⁷ are as defined in claim 5 .
 7. A method according toclaim 1 , wherein the insulin sensitiser is5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dioneor a tautomeric form thereof and/or a pharmaceutically acceptable saltthereof and/or a pharmaceutically acceptable solvate thereof.
 8. Amethod according to claim 7 , wherein the insulin sensitiser is a maleicacid salt of5-[4-[2-(N-methyl-N-(2-pyrdyl)amino)ethoxy]benzyl]thiazolidine-2,4-dioneor a tautomeric form thereof and/or a pharmaceutically acceptablesolvate thereof.
 9. The use of an insulin sensitiser for the manufactureof a medicament for the treatment and/or prophylaxis of renal diseasesincluding diabetic nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, hypertensive nephrosclerosis and endstage renal disease and microalbuminuria.
 10. A pharmaceuticalcomposition for the treatment and/or prophylaxis of renal diseasesincluding diabetic nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, hypertensive nephrosclerosis and endstage renal disease and microalbuminuria which composition comprises aninsulin sensitiser and a pharmaceutically acceptable carrier therefor.